Angucyclines and Angucyclinones from Streptomyces sp.CB01913 Featuring C-ring Cleavage and Expansion

Angucyclines and angucyclinones are aromatic polyketide natural products featuring a tetracyclic benz[a]anthracene skeleton that is distinct from the benz[b]anthracene skeleton found in tetracyclines and anthracyclines.(1) Since the isolation of tetrangomycin, the first angucyclinone discovered, from Streptomyces rimosus in 1965,(2) the angucycline and angucyclinone family of natural products has grown steadily. To date, this family of natural products has been discovered exclusively from actinomycetes, with Streptomyces as the major producers.(1, 2) Representing the largest family of polycyclic aromatic polyketides known to date, angucyclines and angucyclinones feature a characteristic tetracyclic benz[a]anthracene scaffold that is biosynthesized by type II polyketide synthases (PKSs) via decarboxylative condensations of a short acyl-CoA starter and nine extender units.(1) The structural diversity of angucyclines and angucyclinones mainly comes from (i) oxidations on the angular tetracyclic backbone, including hydroxy substitutions at C-4/5/6a/7/12/12a in the saccharothrixins,(3) epoxidation at C-5/6 or C-6a/12a in the panglimycins,(4) or carbonyl substitutions at C-7 and C-12 in the hatomarubigins;(5) (ii) amino acid incorporations, as in the two-point attachment of different amino acids to form yet another ring in jadomycins(6) or of tyrosine and tryptophan into urdamycins C and D;(7) (iii) ring cleavages including A-ring cleavage in the grincamycins,(8) B-ring cleavage in the gilvocarcins,(9) or C-ring cleavage in emycins E and F;(10) and (iv) glycosylation at various positions, such as the multiple trisaccharide units of d-olivose-4-1-d-olivose-3-1-l-rhodinose attached at the O-8 position in the landomycins(11) or deoxysugars attached at the O-3 and C-9 positions in the saquayamycins.(12)
As part of the Natural Products Library Initiative (NPLI) at The Scripps Research Institute (TSRI), dedicated to the discovery of natural products from our Actinomycetales strain collection,(13-17) we report the discovery of 14 angucyclinones and two angucyclines (1–16) from Streptomyces sp. CB01913, including 12 new compounds with (i) various oxidations on rings A and C (1, 2, and 4), (ii) different glycosylations on rings A and B (3 and 6), and (iii) C-ring cleavage (5 and 10–14) and expansion (8). The natural products isolated in this study show unique characteristics compared with known angucyclines and angucyclinones: (i) 9–14 are the only members with C-ring cleavage between C-12 and C-12a; (ii) 5, 7, and 8 represent rare C-ring cleavage or expansion between C-6a and C-7; (iii) 3 and previously reported TAN-1085(2) represent the only two angucyclines with sugar moieties attached at C-6; and (iv) 1, 4, and 6 contain a hydroxy group, instead of the usual carbonyl, at C-12. These new structural features, especially the C-ring cleavage and expansion represented by 5, 8, and 10–14, enrich the structural diversity of the angucycline and angucyclinone family of natural products. All compounds were tested for cytotoxicity and antibacterial activities, with 1, 5, 15, and 16 showing moderate activities against selected cancer cell lines or bacterial strains.